Stimulus responsive polymers undergo a response event which drives the polymer through a phase change within a particular temperature range: the coil-to globule transition (Tc-g). The phase change may be observed directly or may be detected as a change in hydrophilicity or hydrophobicity of the polymer. The lower critical transition temperature (LCST) marks the transition temperature.
WO2010/094976 (Rimmer et al) discloses hyper branched, herein referred as highly branched, hydrophilic thermoresponsive polymers with bacteria binding functionality which can be used to remove infective bacteria from media such as wounds and biofluids. Thermoresponsive polymers belong to the general class of stimulus responsive polymers. These thermoresponsive polymers undergo a binding event on binding bacteria which drives the polymer through the Tc-g.
We have now found that adding these highly branched hydrophilic polymers to otherwise non-active polymeric materials and surfaces is an attractive proposition for conferring bacteria-binding functionality on such materials. However, in many instances simply mixing the functional polymer and non-active polymer material to produce blends produces material that is subject to leaching of the highly branched hydrophilic polymer. This occurs because the highly branched hydrophilic polymer is water-soluble and can generally be extracted into an aqueous phase, precluding application from solution or use in a medical application because of the aqueous environment. Therefore, in order to add such highly branched hydrophilic polymer to structural material used in medical devices it is necessary to prevent it from being leached.
There is therefore a need for a polymeric material comprising non-leachable bacteria binding polymer.
We therefore provide herein a polyurethane material for the detection or sensing of species or stimulus comprising a polyurethane network comprising immobilised therein, or modified by the immobilisation therein of,
a hydrophilic polymer comprising a ligand or moiety for the detection or sensing of species or stimulus by means of fluid contact therewith and comprising immobilised indicator for indicating detection or sensing
wherein species or stimulus is selected from chemical or biological species or stimulus.
Species are preferably selected from acid and base groups and microbes, preferably bacteria, yeast, fungus, and combinations thereof. Stimulus is suitably selected from temperature, pH, ionic strength, hydrophilicity, polarity and species-response.
Detection or sensing is suitably by means of intimate contact with species or stimulus or their environment. The material is preferably for sensing or detecting species or stimulus by means of intimate contact therewith. Immobilised ligand or moiety is bound to the hydrophilic polymer in manner that it remains bound in a fluid environment
Polyurethanes/ureas may be formed by polymerisation of isocyanates and alcohols and/or water. Polyurethane networks such as chain extended or crosslinked polyurethanes may be formed by polymerisation of multi-functional alcohols with diisocyanates. We have now surprisingly found that highly branched hydrophilic bacteria-binding polymer may be immobilised in polyurethanes by mixing in during polyurethane polymerisation, more particularly during or prior to network formation such as during or prior to a chain extending step or a crosslinking step or during a step growth polymerisation step. A polyurethane network appears to grow in the presence of the highly branched hydrophilic polymer. The highly branched hydrophilic polymer appears to become entwined within, and penetrate, the network whereby it is unable to diffuse out of the polyurethane network.
In an extension of this work we have also discovered that corresponding linear or moderately branched hydrophilic polymers and block copolymers thereof may be immobilised by mixing in in similar manner. A polyurethane network appears to grow in the presence of any such hydrophilic polymer. The hydrophilic polymer appears to become entangled within the network whereby it is unable to diffuse out of the polyurethane network.
Preferably ligand or moiety and indicator are immobilised by means of network formation in the presence of hydrophilic polymer or part thereof or an amount thereof in fluid phase, preferably rendered in fluid phase by means of dissolution, solvation or the like.
A polyurethane material may be a stimulus-responsive polyurethane material comprising a polyurethane network modified by the immobilisation therein of a stimulus-responsive hydrophilic polymer.
An indicator such as the fluorescence dye nile red acrylate, covalently attached to the hydrophilic polymer chain backbone, allows for direct fluorescence interrogation of the hydrophobicity of the polymer coil and change in hydrophobicity on undergoing a stimulus response.
Alternatively or additionally a polyurethane material may be a species or stimulus indicating polyurethane material comprising a polyurethane network modified by the immobilisation therein of a hydrophilic polymer comprising an indicator for detection or sensing of species or stimulus. An indicator such as the fluorescence dye nile red acrylate, covalently attached to the hydrophilic polymer chain backbone, allows for direct fluorescence interrogation of the hydrophobicity of the hydrophilic polymer and change in hydrophobicity on detecting or sensing a species or stimulus.
Alternatively or additionally a polyurethane material may comprise a polyurethane network modified by the immobilisation therein of a linear hydrophilic polymer.
Preferably hydrophilic polymer is species-indicating or stimulus indicating hydrophilic polymer.
The polyurethane material may additionally be for monitoring species or stimulus as hereinbefore defined. Polyurethane material for monitoring provides for continuous or periodic sensing or detecting.
The polyurethane material may additionally be for assessing species or stimulus as hereinbefore defined. Polyurethane material for assessing provides for quantitation or qualification of sensing or detecting.
Preferably hydrophilic polymer comprises a ligand or moiety for sensing and/or detection of species or stimulus as hereinbefore defined. Preferably hydrophilic polymer comprises an indicator for indicating detection or sensing.
Preferably the material, and more preferably the hydrophilic polymer immobilised therein, comprises functionality for the detection and/or sensing, and/or binding of species which induce a stimulus response and/or comprises an indicator for a stimulus response. Preferably functionality comprises a ligand or moiety as hereinbefore defined.
The hydrophilic polymer may be highly branched or linear or a part or moiety thereof may be highly branched and a part or moiety thereof may be branched or linear. A highly branched or linear polymer may incorporate a part or moiety which is moderately branched. Such part highly branched part linear hydrophilic polymers are referred herein as extended polymers. Extended hydrophilic polymers are obtained with a first polyurethane reaction step conducted in the presence of a first hydrophilic polymer, the reaction extended with use of a second polyurethane reaction step conducted in the presence of a second hydrophilic polymer.
Highly branched polymer is also termed hyper branched in the art, reference herein to highly branched polymer is to be taken as referring also to such hyper branched polymer.
Reference herein to hydrophilic polymer is to include highly branched hydrophilic polymer, moderately branched hydrophilic polymer, linear hydrophilic polymer or block copolymers thereof herein termed extended hydrophilic polymer unless indicated as only one or several thereof or unless the sense dictates only one or several thereof.
In a further aspect there is provided a novel hydrophilic polymer comprising ligand or species as herein defined comprising at least one block copolymer of a highly branched hydrophilic polymer and a linear hydrophilic polymer as herein defined. Preferably the block copolymer comprises a core block and an outer or peripheral block or blocks. Preferably the block copolymer is characterised by its preparation wherein the core is prepared by the process for preparing one of highly branched and linear hydrophilic polymer and the process terminated and subsequently extended or recommenced following the process for preparing the other of highly branched and linear hydrophilic polymer. The polyurethane material may comprise one hydrophilic polymer or a plurality or blend thereof.
The LCST of the herein defined hydrophilic block polymers is dependent on the block architecture, in particular the architecture of the peripheral block.
Accordingly polyurethane material comprising a plurality or blend of hydrophilic block copolymers is characterised by multiple LCST. Preferably LCST fall in a range with the branched-branched polymers having a much lower LCST than the branched-linear equivalents. The polyurethane material is useful in detecting or sensing and quantifying species or stimulus.
In a further advantage polyurethane material comprising hydrophilic block copolymer providing a distribution of LCST provides for quantitative assessment of species or stimulus, wherein level of detected or sensed response is proportional to the amount of species or degree of proliferation thereof, or the degree of stimulus present.
Further features of the material are defined hereinbelow.
In a particular advantage the material comprises ligand or moiety, in particular comprises bacteria-binding or bacteria detecting ligand or moiety or functionality added to otherwise non-antibiotically active polymeric material. Such material is adapted for enabling in situ identification of bacteria with a non-antibiotically active material.
Without being limited to this theory we believe that the hydrophilic polymer retains the ability to bind bacteria, in addition to detecting or sensing.
Preferably ligand comprises antibiotic or a derivative thereof modified or immobilised or both in manner to be devoid of antibiotic activity or devoid of an ability to reorganise the outer membrane of bacteria, preferably to retain the capacity to sense or detect bacteria.
Suitably the material comprises non-leachable bacteria detecting or sensing and/or binding ligand or moiety or non-leachable bacteria detecting function, more particularly comprises non-leachable bacteria detecting or sensing hydrophilic polymer.
Suitably the material comprises polyurethane material as structural material having hydrophilic polymer comprising bacteria binding or bacteria detecting or sensing ligand or moiety or functionality immobilised within the structural material in manner to prevent the hydrophilic polymer, and more particularly thereby the bacteria detecting or sensing or binding ligand or moiety or functionality or function comprised thereby, from being leached.
Material for sensing and/or assessing and/or detecting microbes such as bacteria, as hereinbefore defined, is not classified as antibiotic material. Accordingly such material may be applied to an environment or a locus such as a wound site without the need for a prescription or other authority to medicate, in particular without the need for a prescription or other authority to apply antibiotic medication.
Preferably therefore such material is not intentionally anti biotic. Preferably the material, hydrophilic polymer and bacteria detecting or sensing ligand or moiety or functionality are configured to interact with live microbes such as bacteria in order to sense, assess or detect the presence thereof, however microbes such as bacteria remain live in contact with the material. Preferably microbes such as bacteria are substantially unchanged by interaction with the material, at least in terms of antibiotic resistance. Without being limited to this theory it is thought that microbes such as bacteria are not disrupted by interaction with the material, at least to an extent that might induce antibiotic resistance, or are not violated or entered as a result of contact with the material, at least to an extent that might induce antibiotic resistance. Preferably the material is not configured to release microbicide such as bactericide which might permanently interact with microbes or bacteria.
Polyurethane material is provided as structural material such as a sheet or layer. Providing as a sheet or layer ensures that polyurethane material is not washed away by water or aqueous media or physiological fluid such as wound fluid. Polyurethane material may thereby be positioned in a locus and retained in position in the locus.
Hydrophilic polymer is immobilised within the polyurethane polymer network as hereinbefore defined. Suitably indicator is immobilised on the hydrophilic polymer, preferably is covalently bound thereto.
Suitably ligand or moiety is immobilised on the hydrophilic polymer, preferably is covalently bound thereto. Reference herein to immobilisation or to a hydrophilic polymer. ligand or indicator being immobilised within or by a component such as the polyurethane polymer network or the hydrophilic polymer is to its presence within or on that component and remaining within or on that component throughout the intended use or lifetime of the material.
Preferably hydrophilic polymer and thereby indicator is distributed throughout the polyurethane material. Hydrophilic polymer and thereby indicator are thus characterised by location within the polyurethane material. Hydrophilic polymer and/or indicator may be associated with or may provide location information. Location information may for example be in the form of a material map. For example indicator may provide location information for indication or change of indication such as a material map of indication or change of indication. Suitably indicator is adapted to detect or sense species or ligand in the direct vicinity thereof.
Preferably hydrophilic polymer, ligand or moiety and/or indicator remain immobilised in the presence of water, aqueous media or physiological fluid and the like at ambient temperature such as in the range 0-45 C, most particularly under physiological conditions. Immobilised hydrophilic polymer, ligand, moiety and/or indicator are thus retained within or on the material. Hydrophilic polymer. Ligand, moiety and/or indicator are thus able to sense, detect or indicate bacteria present or pH at the polyurethane material. Immobilised hydrophilic polymer, ligand, moiety and/or indicator may be retained at one or a plurality of zones within or on the polyurethane material. Hydrophilic polymer, ligand, moiety and/or indicator are thus able to sense, detect or indicate bacteria or pH at the zone.
In a particular advantage the polyurethane material is obtained in a simple manner that involves only blending of hydrophilic polymer with polyurethane reaction components or polymerisation components.
Preferably therefore the hydrophilic polymer is immobilised within the network by introduction during the polymerisation reaction, which may be during formation of prepolymer or step growth of the polyurethane material whereby the hydrophilic polymer is present during the growth of the network, or during chain extension or crosslinking thereof.